Key symptoms in asthma and COPD are the shortness of breath and dyspnea caused by bronchoconstriction, leading to restricted flow of air into the lungs. In conditions such as these, air flow becomes limited as the diameter of the bronchi and bronchioles is reduced in size due to contraction of the airway smooth muscle (ASM) that surrounds those airways. Excessive parasympathetic neural signalling, most likely via cholinergic nerves and corresponding receptors of the ASM, is thought to contribute to such pathological bronchoconstriction.
Small molecule “bronchodilators” reverse contraction of the airway smooth muscle either by acting as agonists for sympathetic neurotransmitter (e.g. catecholamines such as nor-epinephrine and epinephrine) receptors, or by acting as antagonists for the parasympathetic neurotransmitter acetylcholine. For example, beta-adrenoceptor agonists (e.g. salbutamol) act as bronchodilators by activating beta 2 adrenoceptors in airway smooth muscle, which, when activated, cause relaxation of airway smooth muscle. Antimuscarinic bronchodilators (also known as anticholinergics) act by blocking muscarinic receptors in the airway smooth muscle that would otherwise cause bronchoconstriction when activated acetylcholine-mediated parasympathetic signalling.
Modifying the balance between bronchodilatory and brochoconstrictive signalling has formed the basis for a number of treatments of diseases characterised by bronchoconstriction, such as asthma and COPD. In the early 20th century, denervation—severing the nerves that innervate the lung—was investigated as a therapeutic approach to these diseases. However, such methods were crude and, as the vagus nerve controls numerous organs and body functions besides the lungs and respiration, resulted in significant side-effects. Modern attempts to influence the balance on neural signalling through destructive processes such as partial or whole ablation of the nerves may have similar drawbacks. A further approach has been to stimulate the afferent branches of the vagus nerve to signal the adrenal medulla, thereby causing a release of catecholamines which leads to bronchodilation (Hoffmann et al. Neuromodulation 2012; 15: 527-536, which is incorporated herein by reference in its entirety). However, a systemic increase in circulating catecholamines likely has associated side-effects, such as raised heart rate and raised blood pressure.
Additional methods of alleviating bronchoconstriction would be desirable.